1. Field of the Invention
The invention relates to a process for preparing quetiapine and its salts (e.g., quetiapine fumarate). The invention further includes formulating quetiapine and/or its salts (e.g., quetiapine fumarate) (collectively, “the compounds of the invention”) into readily usable dosage units for the therapeutic treatment (including prophylactic treatment) of mammals including humans.
2. Discussion of the Related Art
Quetiapine (Compound I) is the common name for 2-[2-4-Dibenzo[b,f][1,4]thiazepin-11-ylpiperazin-1-yl)ethoxy]ethanol.
Quetiapine fumarate (Compound II) is a commercially marketed pharmaceutically active substance useful for the treatment of schizophrenia. Compound II may be made by a variety of methods.

U.S. Pat. No. 4,879,288 and its equivalent EP 240 228 disclose three general processes for preparing quetiapine and quetiapine fumarate.
According to U.S. Pat. No. 4,879,288 and EP 240 228, and as illustrated in Scheme I (below), one mole of Compound III (i.e., dibenzothiazepinone, dibenzo[b,f][1,4]thiazepine-11(10H)-one) is combined with 14.8 moles of phosphorous oxychloride and 0.6 moles of N,N-dimethylaniline and the mixture is refluxed for about 6 hours. The excess phosphorous oxychloride can then be removed under vacuum to yield a brown residue, which can then be dissolved in toluene and treated with an ice-water mixture. The toluene layer is then separated, washed twice with water and dried with anhydrous magnesium sulphate. After removal of the drying agent by filtration, the filtrate can be concentrated under vacuum to give a 92.6% yield of Compound IV (i.e., 11-chlorodibenzo[b,f][1,4]thiazepine).
Compound IV can then be combined with 2.58 L of xylene and 2 mol of Compound V (i.e., 2-(2-Piperazin-1-ylethoxy)-ethanol) and refluxed for approximately 30 hours. Thereafter, the mixture is subjected to a complex work-up, which includes using diethyl ether, in which Compound I (i.e., quetiapine) is extracted as a dichloromethanic solution. Compound I is then concentrated under vacuum to yield a viscous amber oil which is purified by flash chromatography using a silica gel column and dichloromethane as eluent. The yield of Compound I following purification is 77.7% (overall yield=71.9%).
Compound I (1 mole) is then optionally treated with 1.04 mol of fumaric acid in 3.6 mL of ethanol to yield 49.63% of Compound II (i.e., quetiapine fumarate) (overall yield of quetiapine fumarate=35.7%).
Although the process illustrated in Scheme I is feasible on an industrial scale, it is nonetheless difficult and uneconomical. Specifically, the process of Scheme I requires the use of large amounts of phosphorous oxychloride, which is both highly toxic and environmentally hazardous. Additionally, N,N-disubstituted anilines, such as N,N-dimethylaniline, are similarly dangerous and pose irreversible side effects and can be toxic to aquatic organisms. Similarly, diethyl ether and dichloromethane are toxic materials. In addition to the toxicity of some of the chemicals involved, Scheme I also requires long reaction times and the use of flash and column chromatography to obtain purified products.

A similar process disclosed in U.S. Pat. No. 4,879,288 and EP 240 228 is illustrated in Scheme II (below) in which Compound III is converted to the corresponding thiolactam, Compound VI, followed by conversions to the corresponding thioether, Compound VII. Compound VII is then converted to Compounds I and II via reaction with Compound V.

Another process disclosed in U.S. Pat. No. 4,879,288 and its equivalent EP 240 228 is illustrated in Scheme III (below).

In Scheme III, Compound III is converted to Compound IV via treatment with phosphorous oxychloride (yield=92.6%). Compound IV is then reacted with piperazine to yield 88% of Compound VIII (i.e., 11-piperazin-1-yldibenzo[b,f][1,4]thiazepine·2 HCl). Compound VIII is then reacted with 2-chloroethoxyethanol to yield Compound I (yield=78%) which is in turn readily converted to Compound II (overall yield=63.6%). A phase transfer catalyst can also be used in Scheme III (WO 2004/076431). As with Scheme I, Scheme III is both difficult and uneconomical on a large scale and, in particular, Scheme III requires the use of large quantities of phosphorous oxychloride as well as N,N-dimethylaniline (discussed above).